The following is an interesting summary of reports ffrom the Barcelona
Movement Disorders Conference on the use of PD meds during the initial
years of PD - whether to start treatment with levodopa or a dopamine
agonist, which one, what are the long term implications for both physical
symptoms and quality of life. The report indicates the research is
inconclusive, and neuros do not agree among themselves. Make sure to read
the last 2 paragraphs especially.
My 5 year "birthday" as a diagnosed PWP is Dec. 4. I began taking Sinemet
about 9 months later, and added ReQuip about 3 years ago, decreasing the
Sinemet to a total of 300 mg/day (1 25/100 3x a day). I'm now noticing
ithe beginnings of dyskenesia as predicted. Yet without the Sinemet I
don't think I would have been able to continue to work or do other (more
enjoyable) activities, so I think this was the right decision for me.
I'm wondering what others think, based on your experiences - a discussion
on these isues coould be very helpful to the newly diagnosed, who are
faced with making this difficult decision.
And Happy (?) Election Day to those of us in the U.S.
Linda
The following is from:
http://www.medscape.com/Medscape/Neurology/journal/2000/v02.n05/mn1016.ma
zz/mn1016.mazz-01.html.
Conference Report
Conference Highlights From the Sixth International Congress of
Parkinson's Disease and Movement Disorders
Pietro Mazzoni, MD, PhD, Columbia University
Clinical Trials in PD
Long-term treatment of patients with PD with levodopa is accompanied,
after
a few years, by the apparently inevitable development of motor
complications. These mostly consist of the following:
1. a shortened duration of efficacy (down to as little as 1 to 2
hours),
which leads to "on-off" fluctuations in a patient's motor function;
and
2. dyskinesias, which are continuous involuntary writhing movements of
the face, neck, or limbs.
Whether delaying treatment with levodopa helps to delay or reduce the
severity of these complications remains an unanswered question, leading
to
difficult choices for most patients with PD and their physicians. Most
patients would be willing to forgo use of levodopa for a few years if
this
postponed the onset of motor complications. On the other hand,
withholding
levodopa's sometimes substantial benefit during a period of greatest
activity and productivity would be worthless if the complications appear
independently of the initiation of levodopa treatment.
Dopamine Receptor Agonists
Three studies compared the effects of using a dopamine receptor agonist,
with or without levodopa, to using levodopa alone. The dopamine agonists
most commonly used for PD are pergolide, pramipexole, and ropinirole. All
3
studies compared the rate of development of motor complications in each
treatment group. The design of an ongoing study, comparing early
treatment
with levodopa to placebo treatment, was also described.
Pergolide vs Levodopa
Dr. Wolfgang H. Oertel of Marburg, Germany, reported the results of the
PELMOPET (PErgolide vs Levodopa MOnotherapy with Positron Emission
Tomography [PET] scan) trial.[11] The participants were 44 patients in
the
early stages of PD (Hoehn and Yahr stage 1 to 2) with a demonstrated
response to dopamine receptor stimulation (positive apomorphine test
result), who had not previously been treated with levodopa for more than
2
weeks. They were randomized to be treated with either pergolide alone or
levodopa alone for at least 3 years. After 1 year of treatment, patients
receiving pergolide had significantly fewer and less severe motor
complications than the patients receiving levodopa. However, after 3
years
this difference disappeared. Moreover, the improvement in motor function
provided by the drug was always greater for patients taking levodopa.
The researchers also obtained fluorodopa PET scans of study patients'
brains. Uptake of fluorodopa by the striatum is a measure of PD
progression, decreased uptake correlating with advancing disease. There
was
no significant difference in the decrease in fluorodopa uptake between
the
2 groups of patients. These results suggest that
1. using an agonist instead of levodopa delays the onset of severe
motor
complications;
2. in the long run these complications develop anyway;
3. levodopa may provide better symptom control;
4. there is no difference in disease progression between the 2
treatments.
Pramipexole vs Levodopa
Dr. Ira Shoulson of the University of Rochester, New York, reported the
initial results of the CALM-PD (Comparison of the Agonist pramipexole vs
Levodopa on Motor complications in PD) study.[12] A total of 301 patients
with mild-to-moderate PD, not recently treated with levodopa, were
randomized to blind treatment with either the dopamine receptor agonist
pramipexole or levodopa.
Unlike the previous study, treating physicians were allowed to supplement
the blinded treatment with open-label levodopa if they deemed necessary;
a
similar proportion of patients in each group ended up receiving this
supplementation. After 2 years of treatment, fewer patients in the
pramipexole group developed motor complications compared with patients in
the levodopa group. The levodopa group derived better motor benefit. A
brain imaging scan at the beginning and end of the study showed no
difference in disease progression between the 2 groups (the technique
used
was "beta-CIT" single photon emission computed tomography (SPECT) scan,
an
imaging technique measuring the amount of remaining dopamine transporter
--
also a marker of PD severity).
This study showed after 2 years results similar to the PELMOPET study at
1
year: fewer patients developed motor complications when the initial
treatment is with an agonist rather than levodopa. Remarkably, symptom
control was still better in the levodopa group, even though supplemental
levodopa was used in both groups to optimize treatment. This result
raises
several questions about treatment decisions but cannot be explained at
present. As for the long-term effects of the 2 treatments, clues may come
from a controlled extension of this study currently under way.
Ropinirole vs Levodopa
Dr. Oliver Rascol of the University Hospital in Toulouse, France,
described
various findings of a study comparing ropinirole to levodopa (O56
study).[13] A total of 268 patients were randomized to take ropinirole or
levodopa. The use of supplemental levodopa in either group was permitted
to
maximize symptomatic benefit. Patients were followed up for 5 years. The
incidence of dyskinesia after 5 years was significantly less in the
ropinirole group compared with the levodopa group (20% vs 46%). As for
effectiveness in symptom control, Dr. Rascol emphasized that the
activities
of daily living scores remained similar in the 2 groups. This may explain
why the motor benefit from the dopamine agonist was less than from
levodopa
in the PELMOPET and CALM-PD studies, even though supplemental levodopa
could be given to both groups of patients in these studies. If the
improvement perceived by the patient (as reflected in the activities of
daily living score) was the same, then the difference in motor benefit
scores may not be clinically significant.
Another important finding in this study was that the rate of development
of
dyskinesia was nearly 0 while the patients were taking ropinirole alone.
Most motor complications developed after supplementary levodopa was added
to the therapy. In addition, the progression of the dyskinesias after the
addition of levodopa was not faster than for the patients taking levodopa
alone. Thus, the benefit of using ropinirole as initial treatment is
maintained even after dyskinesias develop.
Earlier vs Later Levodopa
Intertwined with the question of whether early PD treatment should be
with
an agonist or levodopa is another old but as yet unanswered question --
whether delaying the start of treatment with levodopa has any influence
on
the development of motor fluctuations or on the course of the disease
itself. Dr. Stanley Fahn of Columbia University in New York, NY, outlined
the design of the ELLDOPA (Earlier vs Later Levodopa therapy) study, an
ongoing study addressing the latter question.[14]
A total of 360 patients in the early stages of PD are being randomized to
receive levodopa therapy or placebo for 9 months. After this period they
will be reexamined, and the change in severity of parkinsonism from
before
entering the study will be compared in the 2 groups. If levodopa, as has
been widely thought, indeed provides only relief of symptoms and does not
affect the course of PD, then the change in examination should be the
same
in both groups. Moreover, in a smaller group of patients the amount of
neurodegeneration that takes place during the 9 months of the study will
be
assessed by comparing beta-CIT PET scans before and after treatment in
each
group.
Medical Therapies in PD
New vs Old Dopamine Agonists
This session consisted of point-counterpoint style presentations on each
side of 2 major current debates in this field. One subject was whether
the
new dopamine agonists (ropinirole, pramipexole, and cabergoline) are
better
than older ones (bromocriptine and pergolide). Dr. Donald B. Calne of the
University of British Columbia in Vancouver, Canada, presented the
arguments for the positive answer.[15] One of the main arguments is that
the new agonists are at least designed to be more selective than the
older
ones in their action on dopamine receptors. Such selectivity often
implies
higher efficacy and lower frequency and range of adverse effects. Whether
these advantages are real and clinically significant, unfortunately, has
not been demonstrated, since there have been no direct comparisons of
efficacy and adverse effect profiles between the new and the old
agonists.
Dr. Anthony E. Lang of the Toronto Western Hospital in Toronto, Canada,
argued that the new dopamine agonists are not better than the old
ones.[16]
He focused on what "better" really means in this context. He argued that
it
is not yet clear whether efficacy, ease of use, or adverse effect profile
are any better for the new agonists. He also pointed out that the new
drugs
are much more expensive than the old ones, and this should be included in
the assessment of which drug should be used -- at least until definitive
studies establish a medical advantage for one drug over another.
What Should Be the Initial Drug?
Immediately following the discussion of new vs old dopamine agonists was
a
debate on whether treatment of PD should begin with agonists or levodopa.
On this issue, Dr. S. Gimenez-Roldan of the Hospital General
Universitario
Gregorio Maranon, Madrid, Spain argued in favor of starting with
agonists.[17] One argument for this position can now be considered
evidence
based: 3 studies described in the previous session found 3 agonists to
delay the onset of motor complications associated with levodopa therapy.
Another argument has been suggested by theories and laboratory evidence
on
the mechanisms of neurodegeneration in PD: dopamine receptor agonists may
have a neuroprotective effect. This protection has been postulated to
result through a variety of mechanisms, including autoreceptor
stimulation,
direct antioxidant effects, and decrease of subthalamic nucleus
excitotoxicity. Dr. Gimenez-Roldan cautioned that starting treatment with
agonists is not a blanket recommendation applicable to all patients with
PD, since several factors (such as age and cognitive status) may steer
the
choice to levodopa instead for certain patients.
Dr. Andrew J. Lees of the National Hospital for Neurology and
Neurosurgery
in Queen Square, London countered that treatment of PD should start with
levodopa in all but those patients with young-onset PD.[18] He focused on
the objective of maximizing quality of life throughout this illness. He
reminded the audience that levodopa maintains its effectiveness much
longer
than any agonists. His main reason to avoid using agonists in the first
few
years was that agonists are associated with a higher rate of adverse
effects.
This point was questioned by Dr. Rascol, who pointed out that the rate of
adverse effects was not significantly different between a dopamine
agonist
and levodopa in the PELMOPET, CALM-PD, or O56 studies. However, it is a
widely accepted teaching that, for a given frequency of adverse effects,
levodopa is more potent than any agonist in relieving PD symptoms. This
belief is not, in fact, contradicted by the agonist studies: as described
above, in the 2 studies that compared the motor examination scores,
levodopa was more effective than the respective agonist.
Dr. Lees' argument included consideration of an issue sometimes
overlooked
in this debate: the first few years of the disease, though marked by
relatively mild symptoms, are also years during which many patients
continue working or have a chance to enjoy activities, such as traveling,
which they may need to give up later. Thus, treatment with a more potent
drug, as levodopa appears to be, may offer a more appreciable improvement
in quality of life than an agonist might. In part because of this
consideration, the question of whether levodopa is indeed more "potent"
--
meaning providing greater relief for a given risk of adverse effects and
for a given ease of use -- was discussed with some interest. No one at
the
session offered a convincing explanation of why, in 2 of the agonist
studies, the motor examination scores improved more for patients taking
levodopa than for patients taking an agonist plus levodopa.
After the debates, the audience was asked to express their opinion via a
show of hands. Most audience members agreed that the new agonists are not
clearly better than the old ones. More surprisingly, most also supported
starting treatment of PD with levodopa rather than an agonist. This was
remarkable because the 3 studies showed a clear delay in the onset of
motor
complications in patients treated with an agonist as initial therapy. A
possible explanation is that ease of use (some agonists require a much
slower titration of dose than levodopa before reaching the same
effectiveness) and rate of adverse effects, at least as experienced by
clinicians in their practice, may play a bigger role in a practicing
clinicians' choices than in the conclusions of a drug study.
Perhaps the most relevant comment, sobering as it was, was made by Dr.
Lees
at the end of the discussion. He pointed out that when considering the
entire course of PD, which can span several decades, the first 5 years
are
usually marked by relatively minor symptoms that can be controlled
adequately with either levodopa or an agonist. As he put it, "the first 5
years are easy" in terms of treatment choices. The much more difficult
period is the following years, during which motor fluctuations, variation
in response to levodopa, and the progression of symptoms refractory to
levodopa take a more serious toll on the quality of life of patients with
PD than in the first 5 years. Thus, without denying the importance of
making the best use of the treatment options that we have for the initial
period, he expressed hope that the search will continue for better
treatments for the more advanced stages of PD.
